Department of Cardiology, Zhongshan Hospital, Fudan University, No. 180 of Road Fenglin, District Xuhui, Shanghai, 200032, China.
Research Unit of Cardiovascular Techniques and Devices, Chinese Academy of Medical Sciences, Shanghai, China.
Hum Genomics. 2022 Sep 7;16(1):36. doi: 10.1186/s40246-022-00405-z.
Bicuspid aortic valve (BAV) is the most common congenital heart defect in human beings, with an estimated prevalence in the general population of between 0.5 and 2%. Moreover, BAV is the most common cause of aortic stenosis in the pediatric population. Patients with BAV may have no symptoms for life, and some of them may progress to aortic stenosis. Genetic factors increase the susceptibility and development of BAV. However, the pathogenesis and BAV are still unclear, and more genetic variants are still needed for elucidating the molecular mechanism and stratification of patients. The present study carried out screening of variants implicated in disease in BAV patients. The whole-exome sequencing (WES) was performed in 20 BAV patients and identified 40 different heterozygous missense mutations in 36 genes (MIB2, FAAH, S100A1, RGS16, MAP3K19, NEB, TTN, TNS1, CAND2, CCK, KALRN, ATP10D, SLIT3, ROS1, FABP7, NUP205, IL11RA, NPR2, COL5A1, CUBN, JMJD1C, ANXA7, TRIM8, LGR4, TPCN2, APOA5, GPR84, LRP1, NCOR2, AKAP11, ESRRB, NGB, AKAP13, WWOX, KCNJ12, ARHGEF1). The mutations in these genes were identified as recurrent variants implicated in disease by in silico prediction tool analysis. Nine genes (MIB2, S100A1, TTN, CCK, NUP205, LGR4, NCOR2, ESRRB, and WWOX) among the 36 genes were identified as variants implicated in disease via unanimous agreement of in silico prediction tool analysis and sequenced in an independent cohort of 137 BAV patients to validate the results of WES. BAV patients carrying these variants demonstrated reduced left ventricular ejection fractions (LVEF) (63.8 ± 7.5% vs. 58.4 ± 5.2%, P < 0.001) and larger calcification volume [(1129.3 ± 154) mm vs. (1261.8 ± 123) mm, P < 0.001]. The variants in TTN, NUP205 and NCOR2 genes are significantly associated with reduced LVEF, and the variants in S100A1, LGR4, ESRRB, and WWOX genes are significantly associated with larger calcification volume. We identified a panel of recurrent variants implicated in disease in genes related to the pathogenesis of BAV. Our data speculate that these variants are promising markers for risk stratification of BAV patients with increased susceptibility to aortic stenosis.
二叶式主动脉瓣（BAV）是人类最常见的先天性心脏缺陷，估计在普通人群中的患病率为 0.5%至 2%。此外，BAV 是儿科人群中主动脉瓣狭窄最常见的原因。BAV 患者可能终生无症状，其中一些患者可能进展为主动脉瓣狭窄。遗传因素增加了 BAV 的易感性和发展。然而，BAV 的发病机制仍不清楚，需要更多的遗传变异来阐明其分子机制和患者分层。本研究对 BAV 患者中涉及疾病的变异进行了筛选。对 20 名 BAV 患者进行了全外显子组测序（WES），在 36 个基因中发现了 40 种不同的杂合错义突变（MIB2、FAAH、S100A1、RGS16、MAP3K19、NEB、TTN、TNS1、CAND2、CCK、KALRN、ATP10D、SLIT3、ROS1、FABP7、NUP205、IL11RA、NPR2、COL5A1、CUBN、JMJD1C、ANXA7、TRIM8、LGR4、TPCN2、APOA5、GPR84、LRP1、NCOR2、AKAP11、ESRRB、NGB、AKAP13、WWOX、KCNJ12、ARHGEF1）。通过计算机预测工具分析，这些基因中的突变被确定为涉及疾病的复发性变异。在 36 个基因中，有 9 个基因（MIB2、S100A1、TTN、CCK、NUP205、LGR4、NCOR2、ESRRB 和 WWOX）通过计算机预测工具分析的一致意见和在 137 名 BAV 患者的独立队列中的测序被确定为涉及疾病的变异，以验证 WES 的结果。携带这些变异的 BAV 患者的左心室射血分数（LVEF）降低（63.8±7.5%比 58.4±5.2%，P<0.001），钙化体积增大[（1129.3±154）mm 比（1261.8±123）mm，P<0.001]。TTN、NUP205 和 NCOR2 基因中的变异与 LVEF 降低显著相关，S100A1、LGR4、ESRRB 和 WWOX 基因中的变异与更大的钙化体积显著相关。我们确定了一组与 BAV 发病机制相关的基因中涉及疾病的复发性变异。我们的数据推测，这些变异是 BAV 患者主动脉瓣狭窄易感性增加的风险分层的有前途的标志物。
